In this renewal application, we have moved from dual-energy x-ray absorptiometry (DXA) to novel assessments of volumetric bone mineral density (vBMD), structure, and indices of bone strength by quantitative computed tomography (QCT) of the vertebrae and proximal femur and ultra-high resolution, peripheral QCT of the distal radius. In addition, new collaborations with Drs. Tony Keaveny (UC-Berkeley) and Ralph Muller (Swiss Federal Institute of Technology) will allow us to use QCT for voxel-based finite element (FE) models to assess bone "strength" for the first time in population studies. Moreover, in collaborations with Drs. Mary Bouxsein (Harvard) and Kenton Kaufman (Mayo), we will combine estimates of bone strength with assessments of skeletal loading to elucidate the relationship between bone structure and loads. Our central hypotheses are: (1) Age-related changes in bone mass/structure can be accounted for, in large part, by specific hormonal/biochemical parameters, loading forces, and the interactions between them;and (2) Bone strength estimates that can now be obtained clinically will enhance the ability to identify subjects at increased fracture risk. These hypotheses will be tested in our Specific Aims: (1) To continue the cross-sectional and longitudinal (to 6 yrs of follow-up) analysis of our established cohort of Rochester, MN residents (age-stratified sample of 375 women and 325 men, age 20-97 yrs), to better understand bone structural changes with aging (AIM 1a);to relate these changes to sex steroid/biochemical parameters and to estrogen receptor and aromatase polymorphisms (AIM 1b);and to determine the relationship of everyday loading forces to changes in vBMD, bone geometry, and microstructure (AIM 1c);(2) In population-based, case-control studies of postmenopausal Rochester women with vertebral and distal forearm fractures, to use the FE models to quantify bone strength at the spine and distal radius and define the key structural determinants of strength at each site (AIM 2a);to use measures of bone failure strength from FE models to improve current estimates of the "factor-of-risk" (phi, the ratio of applied load to that known to cause bone failure, i.e., fracture) for the vertebrae during various activities and to develop them for the distal radius with falls (AIM 2b);and to determine the utility of our new approaches in differentiating fracture cases from controls in comparison with conventional risk assessment using DXA (AIM 2c).